| First Author | Davis LC | Year | 2020 |
| Journal | EMBO J | Volume | 39 |
| Issue | 14 | Pages | e104058 |
| PubMed ID | 32510172 | Mgi Jnum | J:336348 |
| Mgi Id | MGI:6706168 | Doi | 10.15252/embj.2019104058 |
| Citation | Davis LC, et al. (2020) NAADP-regulated two-pore channels drive phagocytosis through endo-lysosomal Ca(2+) nanodomains, calcineurin and dynamin. EMBO J 39(14):e104058 |
| abstractText | Macrophages clear pathogens by phagocytosis and lysosomes that fuse with phagosomes are traditionally regarded as to a source of membranes and luminal degradative enzymes. Here, we reveal that endo-lysosomes act as platforms for a new phagocytic signalling pathway in which FcgammaR activation recruits the second messenger NAADP and thereby promotes the opening of Ca(2+) -permeable two-pore channels (TPCs). Remarkably, phagocytosis is driven by these local endo-lysosomal Ca(2+) nanodomains rather than global cytoplasmic or ER Ca(2+) signals. Motile endolysosomes contact nascent phagosomes to promote phagocytosis, whereas endo-lysosome immobilization prevents it. We show that TPC-released Ca(2+) rapidly activates calcineurin, which in turn dephosphorylates and activates the GTPase dynamin-2. Finally, we find that different endo-lysosomal Ca(2+) channels play diverse roles, with TPCs providing a universal phagocytic signal for a wide range of particles and TRPML1 being only required for phagocytosis of large targets. |
